Thieno[2,3-b-indole derivatives and their use for treating central nervous system diseases related to the metabotropic glutamate receptor system

ABSTRACT

The present invention relates to therapeutically active heterocyclic compounds, a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful in treating diseases in the central nervous system related to the metabotropic glutamate receptor system.

The present invention relates to therapeutic activethieno[2,3-b]indoles, a method for preparing the same, pharmaceuticalcompositions comprising the compounds and a method of treatingtherewith.

Recent molecular biological studies have clearly established theexistence of two major types of glutamate receptors in the centralnervous system namely the ionotropic and the metabotropic glutamatereceptors. The latter is characterised by being G-protein-linked tochanges in second messenger formation and modulation of ion channelfunction, (Meldrum, B. (1991) Epilepsy Res. 10, 55-61, Chapman, A.(1991) in Excitatory Amino Acids p. 265-286, Blackwell scientific publ.ltd., Oxford).

At present 6 different subtypes of the metabotropic glutamate receptorsare described (MGluR₁ to MGluR₆) and in addition some spliced variantsof the subtypes are reported.

The metabotropic glutamate receptor subtypes MGluR₁ and MGluR₅ arecoupled to phosphoinositide hydrolysis (Johnson, G. and Bigge, C. F.(1991) Annu. Rep. Med. Chem. 26, 11-22, Hansen, J. J. andKrogsgaardLarsen, P. Med. Res. Rev. 10,55-94, Thomsen, C. and Suzdak, P.(1993) Eur. J. Pharmacol. 245, 299), while the others are coupled tocyclic AMP formation (Schoepp, D. D., Johnson, B. G. and Monn, J. A.(1992) J. Neurochem. 58, 1184-1186, Cartmell et al. (1992) J. Neurochem.58, 1964-1966, Manzoni, O. et al. (1992) Eur. J. Pharmacol. 225,357-358).

Compounds such as L-glutamate, quisqualate and ibotenate are known toact as non-selective agonists on the metabotropic glutamate receptors,while selective ionotropic glutamate receptor agonists such as NMDA,AMPA and kainate do have little effect on these receptors.

Recently a few compounds without activity at the ionotropic glutamatereceptors but with activity at the metabotropic receptors have beenidentified.

These comprise trans-ACPD (trans1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid), the partial agonistL-AP3 (L-2-amino-3-phosphonopropionic acid) (Palmer, E., Monaghan, D. T.and Cotman, C. W. (1989) Eur. J. Pharmacol. 166, 585-587, Desai, M. A.and Conn, P. J. (1990) Neurosci. Lett. 109, 157-162, Schoepp, D. D. etal. (1991), J. Neurochem. 56, 1789-1796, Schoepp D. D. and Johnson B. G.(1989), J. Neurochem. 53, 1865-1613), L-AP4(L-2-amino-4-phosphonobutyrate) which is an agonist at the MGluR₄receptor (Thomsen C. et al. (1992), Eur. J. Pharmacol. 227, 361-362) andsome of the isomers of CCG (2-(carboxycyclopropyl)glycines) especiallyL-CCG-I and L-CCG-II (Hayashi, Y. et al. (1992), Br. J. Pharmacol. 107,539-543).

Very few selective antagonists at the metabotropic glutamate receptorshave been reported, however some phenylglycine derivatives S-CPG(S-4-carboxyphenyl glycine), S-4C3HPG (S-4-carboxy-3-hydroxyphenylglycine) and S-MCPG (S-alpha methyl-4-carboxyphenyl glycine) have beenreported to antagonise trans ACPD stimulated phosphoinositide hydrolysisand thus possibly acting as antagonists at the metabotropic glutamatereceptors at the subtypes MGluR₁ and MGluR₅ (Thomsen, C. and Suzdak, P,(1993) Eur. J. Pharmacol. 245, 299).

Literature evidence suggests that compounds selective for themetabotropic glutamate receptors either as agonists or antagonists areuseful in the treatment of different neurological diseases.

The use of compounds active at the metabotropic glutamate receptors forthe treatment of epilepsy is corroborated by investigations of theinfluence of trans-ACPD in the formation of convulsions (Sacaan andSchoepp, (1992), Neurosci. lett. 139, 77) and that phosphoinositidehydrolysis mediated via MGluR is increased after kindling experiments inrats (Akiyama et al. (1992),Brain Res. 569, 71).

Trans-ACPD has been shown to increase release of dopamine in the ratbrain which indicates that compounds acting on the metabotropicglutamate receptors might be usable for the treatment of Parkinson'sdisease and Huntington's Chorea (Sacaan et al. (1992), J. Neurochem. 59,245).

The use of compounds active at the metabotropic glutamate receptors fortreatment of neurological diseases such as senile dementia has beenindicated by the findings of Zheng and Gallagher ((1992), Neuron 9, 163)and Bashir et al. ((1993), Nature 363, 347) who demonstrated thatactivation of metabotropic glutamate receptors are necessary for theinduction of long term potentiation (LTP) in nerve cells (septalnucleus,hippocampus) and the finding that long term depression isinduced after activation of metabotropic glutamate receptors incerebellar granule cells (Linden et al. (1991), Neuron 7,81).

Investigations also show that in the treatment of deficiencies of mentaland motoric performance seen after conditions of brain ischemia themetabotropic glutamate receptor active compounds may prove usable.

Trans-ACPD has been shown to be a neuroprotective agent in an MCAO modelin mice (Chiamulera et al. (1992), Eur. J. Pharmacol. 215, 353), and ithas been shown to inhibit NMDA induced neurotoxicity in nerve cellcultures (Koh et al., (1991), Proc. Natl. Acad. Sci. USA 88, 9431).

Also in the treatment of pain the metabotropic glutamate receptor activecompounds seem of interest, proved by the fact that antagonists at themetabotropic glutamate receptors antagonises sensory synaptic responseto noxious stimuli of thalamic neurons (Eaton, S. A. et al. (1993), Eur.J. Neurosci. 5, 186).

The above findings support that compounds acting on the metabotropicglutamate receptors are useful for the treatment of epilepsy,neurological diseases such as senile dementia, Parkinson's disease,Huntington's Chorea, pain and deficiencies of mental and motoricperformance seen after conditions of brain ischemia.

We have now discovered a series of new thieno[2,3-b]indoles which arepotent antagonists at the metabotropic glutamate receptors.

The present invention relates to compounds of formula I ##STR1## whereinR¹ is H, C₁₋₆ -alkyl optionally substituted with halogen, C₂₋₆ -alkenyl,C₂₋₆ -alkynyl, C₃₋₆ -cycloalkyl, C₁₋₄ -alkyl substituted with C₃₋₆-cycloalkyl, carboxy,--COR⁹, --COR⁹, C₁₋₄ -alkyl substituted withdimethylamino,--R⁹ --O--R¹⁰, --R⁹ --O--R¹¹, phenylsulfonyl,.benzoyl,benzyl or phenyl each of which aromatic group is optionally substitutedwith C₁₋₄ -alkyl, C₁₋₄ -alkoxy, halogen, carboxy or nitro, wherein R⁹,R¹⁰ and R¹¹ are independently C₁₋₆ -alkyl;

R² is H, carboxy, cyano, nitro, C₁₋₆ -alkyl optionally substituted withhydroxy, --R⁹ --O--R¹⁰, --COOR⁹, morpholinocarbonyl,thiamorpholinocarbonyl, piperazinylcarbonyl optionally substituted withC₁₋₄ -alkyl, tetrazolyl, oxadiazolyl or thiadiazolyl optionallysubstituted with C₁₋₄ -alkyl or C₃₋₆ -cycloalkyl, morpholinomethyl,amino unsubstituted or mono or disubstituted with C₁₋₆ -alkyl,methylamino unsubstituted or N-mono or disubstituted with C₁₋₆ -alkyl,sulfamoyl unsubstituted or mono or disubstituted with C₁₋₆ -alkyl orcarbamoyl unsubstituted or mono or disubstituted with C₁₋₆ -alkyl whichalkyl group(s)is/are independently optionally substituted withdimethylaminomethyl, halogen, phenyl or benzyl;

R³ is H, C₁₋₆ -alkyl, trifluoromethyl, trifluoroacetyl, C₁₋₆ -alkoxy,halogen, nitro, cyano, --COOR⁹ or amino unsubstituted or mono ordisubstituted with C₁₋₆ -alkyl;

R⁴, R⁵, R⁶ and R⁷ are independently H, nitro, amino, halogen, tritium,trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl, sulfamoyl,--COR⁹, --COOR⁹, C₁₋₆ -alkoxy, C₁₋₆ -alkyl optionally substituted withhalogen;

or a salt thereof with a pharmaceutically acceptable acid or base.

Alkyl, alkenyl and alkynyl are intended to mean a straight or branchedalkyl, alkenyl or alkynyl chain.

These salts include pharmaceutically acceptable acid addition salts,pharmaceutically acceptable metal salts or optionally alkylated ammoniumsalts, such as hydrochloric, hydrobromic, hydroiodic, phosphoric,sulfuric, trifluoroacetic, trichloroacetic, oxalic, maleic, pyruvic,malonic, succinic, citric, mandelic, benzoic, cinnamic, methanesulfonic,ethane sulfonic, picric and the like, and include acids related to thepharmaceutically acceptable salts listed in Journal of PharmaceuticalScience, 66, 2 (1977) and incorporated herein by reference, or lithium,sodium, potassium, magnesium and the like.

The invention also relates to a method of preparing the above mentionedcompounds. These methods comprise

a) reacting a compound of formula II ##STR2## prepared by well-knownmethods, wherein R¹, R⁴, R⁵, R⁶ and R⁷ have the meanings defined above,with an N,N-dimethyl amide, preferably formamide, and POCl₃ usingVilsmeyer-Hack conditions, to form a compound of formula III ##STR3##wherein R⁸ is H or methyl and R¹, R⁴, R⁵, R⁶ and R⁷ have the meaningsdefined above; and subsequently

b) reacting a compound of formula III wherein R¹, R⁴, R⁵, R⁶, R⁷ and R⁸have the meanings defined above with methyl mercaptoacetate to form acompound of formula IV ##STR4## wherein R¹, R⁴, R⁵, R⁶, R⁷ and R⁸ havethe meanings defined above; and subsequently

c) reacting a compound of the formula IV wherein R¹, R⁴, R⁵, R⁶, R⁷ andR⁸ have the meanings defined above by means of well-known chemicalreactions transforming the methylester group to other functional groupssuch as acids, esters, amides, amines or reaction products thereof asdescribed for the R² substituent, to form a compound of formula Iwherein R¹, R², R⁴, R⁵, R⁶ and R⁷ have the meanings defined above and R³iS H or methyl; or

d) reacting a compound of formula I ##STR5## wherein R¹ is H and R², R³,R⁴, R⁵, R⁶ and R⁷ have the meanings defined above with R¹ -Y wherein R¹has the meaning defined above and Y is a leaving group such as halogenor sulphonate, using strong base as e.g. metal hydrides to form acompound of formula I wherein R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ have themeanings defined above provided that R¹ is not H; or

e) reacting a compound of the formula III ##STR6##

wherein R¹ is H and R⁴, R⁵, R⁶, R⁷ and R⁸ have the meanings definedabove with a compound R¹ -Y wherein Y is a leaving group such as e.g.halogen or sulphonate, using strong base such as e.g. metalhydrides toform a compound of formula III wherein R¹, R⁴, R⁵, R⁶, R⁷ and R⁸ havethe meanings defined above provided that R¹ is not H; or

f) reacting a compound of formula I wherein R¹, R² and R³ have themeanings defined above and at least one of R⁴, R⁵, R⁶ or R⁷ is H withwell known reactive substrates leading to aromatic substitution usingthe reaction conditions known in the art, to form a compound of formulaI wherein R⁴, R⁵, R⁶ and R⁷ have the meanings defined above providedthat at least one of R⁴, R⁵, R⁶ or R⁷ is not H; or

g) a compound of formula I with different R⁴, R⁵, R⁶ and R⁷ groups couldbe prepared by using conventional organic chemistry on functional groupsalready introduced as R⁴, R⁵, R⁶ and R⁷ groups.

The pharmacological properties of the compounds of the invention can beillustrated by determining their effects in different conventionalradioligand binding assays or in functional in vitro assays.

The compounds of the invention were studied in an in vitro assay formeasuring inhibition of PI-hydrolysis in BHK 570 cells expressing mGluR₁α receptors.

Principle

The metabotropic glutamate receptor (mGluR) is selectively activated bytrans-aminocyclopentane dicarboxylic acid and is coupled to thehydrolysis of inositol phosphates via a GTP-binding protein. At themolecular level, cDNAs encoding six subtypes of the mGluR family havebeen isolated. The first subtype isolated (Houamed et al., 1991, Science252, 1318), termed the mGluR1α, has been shown to be coupled toPI-hydrolysis when expressed in baby hamster kidney cells (BHK) (Thomsenet al., Brain Res. (in press)). In these cells no stimulation by 1 mMquisqualate or glutamate was observed with control BHK cells whereas a6-8 fold increase over basal PI-hydrolysis was seen with BHK cellsexpressing mGluR1α.

Cell culture

BHK570 cells expressing mGluR1α are cultured in DMEM (4.5 g/l glucose,2ram glutamin); 5% foetal calf serum; 0.10 mg/ml neomycin; 0.5 mg/mlG418; 1 μM methotrexate; 50 pg/ml gentamycin. Cells are subculturedevery 5 days using 0.05% trypsin/EDTA in PBS.

Inositol phosphate formation

The protocol for PI-hydrolysis was measured using a modification of amethod previously described (Berridge et al., 1982, Biochem. J.206,587). Cells were plated in 16 mm wells (24 well multidish, Costar)with 1 confluent 100 mm dish per multidish. Replace the medium 24 hbefore the experiment with 500 μl fresh growth medium containing 4μCi/mlmyo-[2-³ H]inositol (specific activity 18 Ci/mmol, Amersham). The cellswere washed twice with Krebs-Henseleit buffer (Sigma cat.#3753: glucose2.0 g/l, MgSO₄ 0.141 g/l, KHPO₄ 0.16 g/l, KCl 0.35 g/l, NaCl 6.90 g/land NaHCO₃ 2.1 g/l) supplemented with 10 mM LiCl and 2.5 mM CaCl₂. Thebuffer was equilibrated with 5% CO₂, 95% air to pH 7.5 at 37° C.Following 5 min of preincubation in the above buffer, buffer or testcompounds were added and cells were incubated for 30 rain at 37° C. Inantagonist studies, add test compounds 5 min prior to agoniststimulation. PI-formation was stopped by placing the cells on ice andquickly aspirating the media. The wells were washed once with ice-coldKrebs-Henseleit buffer and subsequently 1 ml ice-cold 10% perchloricacid was added to each well. Place the cells on ice for 20 min. In Nuncminisorp test tubes (75 ×12 mm, cat. #443990): add 250 μl of 10 mM EDTA,pH 7.0+5% Universal Indicator (Merck). Transfer the PCA extract to eachtube containing the pH-indicator. Neutralize the samples with 1.5MKOH+60 mM HEPES to pH 7.5 (˜1100-1200 μl). Centrifugate (6.000 rpm, 5min, 0° C.). They can be stored frozen at this point. Fractions ofinositolphosphates were separated using ion-exchange columns (Amersham,RPN 1908) according to the method provided by Amersham.

Separation of inositol phosphates on ion-exchange columns

Prepare columns with 5 ml 1M KHCO₃ and wash with 15 ml dist. water.Adjust vacuum so that the flow-rate does not exceed 5 ml/min. Add 4 mldist. water and subsequently 1 ml [³ H]InsP sample. Wash with 5 ml dist.water. IP1 to IP4 fractions may be collected with 5 ml 0.05; 0.10; 0.17and 0.25M KHCO₃, respectively. Usually IP1 and IP2 fractions arecollected simultaneously. Scintillation liquid: use 12-15 ml Ultima Gold(Packard).

Testprocedure

Testcompounds are dissolved in DMSO, DMSO and Pluronic F-127 or ethanoland diluted in assay buffer. Glutamate (10 μM and 1000 μM) and bufferalone are included as a control.

Results

The stimulation by 10 μM shall represent a submaximal stimulation. Theresponse by 10 μM glutamate should exceed 3-fold the basal level andshould be below maximal stimulation (glutamate at 1 mM). The results arecalculated relative to be stimulation by 10 μM glutamate and a doseresponse curve is generated.

Examples of test results obtained by testing some compounds of thepresent invention in the above mentioned assay appear from the followingTable 1.

                  TABLE 1                                                         ______________________________________                                        Compound No.    IC.sub.50 (uM)                                                ______________________________________                                        27              5.3                                                            8              21.0                                                          54              7.2                                                           31              36.0                                                          25              9.0                                                           ______________________________________                                    

The compounds according to the invention are effective over a widedosage range. For example, in the treatment of adult humans, dosagesfrom about 0.05 to about 100 mg, preferably from about 0.1 to about 100mg, per day may be used. A most preferable dosage is about 10 mg toabout 70 mg per day. In choosing a regimen for patients suffering from adisease in the central nervous system related to the metabotropicglutamate receptor system it may frequently be necessary to begin with adosage of from about 30 to about 70 mg per day and when the condition isunder control to reduce the dosage as low as from about 1 to about 10 mgper day. The exact dosage will depend upon the mode of administration,form in which administered, the subject to be treated and the bodyweight of the subject to be treated, and the preference and experienceof the physician or veterinarian in charge.

The route of administration may be any route, which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral or parenteral e.g. rectal, transdermal,subcutaneous, intravenous, intraurethral, topical, intramuscular,intranasal, ophthalmic solution or an ointment, the oral route beingpreferred.

Typical compositions include a compound of formula I or apharmaceutically acceptable acid addition salt thereof, associated witha pharmaceutically acceptable carrier. In making the compositions,conventional techniques for the preparation of pharmaceuticalcompositions may be used. For example, the active compound will usuallybe mixed with a carrier, or diluted by a carrier, or enclosed within acarrier which may be in the form of a ampoule, capsule, sachet, paper,or other container. When the carrier serves as a diluent, it may besolid, semi-solid, or liquid material which acts as a vehicle,excipient, or medium for the active compound. The active compound can beadsorbed on a granular solid container for example in a sachet. Someexamples of suitable carriers are water, salt solutions, alcohols,polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine,lactose, amylose, magnesium stearate, talc, silicic acid, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,hydroxymethylcellulose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired,with auxiliary agents, emulsifiers, salt for influencing osmoticpressure, buffers and/or coloring substances and the like, which do notdeleteriously react with the active compounds.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrieror binder or the like are particularly suitable for oral application.Preferable carriers for tablets, dragees, or capsules include lactose,corn starch, and/or potato starch. A syrup or elixir can be used incases where a sweetened vehicle can be employed.

Generally, the compounds are dispensed in unit form comprising fromabout 1 to about 100 mg in a pharmaceutically acceptable carrier perunit dosage.

A typical tablet, appropriate for use in this method, may be prepared byconventional tabletting techniques and contains:

    ______________________________________                                        Active compound                                                                              5.0        mg                                                  Lactosum       67.8       mg Ph.Eur.                                          Avicel ®   31.4       mg                                                  Amberlite ®                                                                              1.0        mg                                                  Magnesii stearas                                                                             0.25       mg Ph. Eur.                                         ______________________________________                                    

The invention will now be described in further detail with reference tothe following examples.

EXAMPLE 1 2-Chloroindole-3-carbaldehyde (1)

POCl₃ (100 ml) was added dropwise to a mixture of dry DMF (100 ml) anddichloromethane (100 ml) kept at 0° C. Indolone (50 g) dissolved indichloromethane (200 ml) and pyridine (50 ml) was added dropwise at

0° C. over a period of 1.5 h. Subsequent stirring at 0° C. for 1 h. Themixture was poured onto icewater (2000 ml) neutralised with NaHCO₃whereafter the mixture was stirred overnight. The aqueous phase wasdecanted and the organic phase evaporated followed by extraction withethanol (boiling). The ethanolic phase was evaporated and thecrystalline residue recrystallized from ethanol yielding 70 g of (1),m.p. 227° C.

1-Benzyl-2-chloroindole-3-carbaldehyde (2)

(1) (10 g) was added to a slurry of Nail (2.7 g) in dry DMF (100 ml),subsequently benzyl bromide (9.52 g) was added to the mixture andstirring was continued at RT overnight. Benzyl bromide (2.9 g) was addedand stirring was continued for 4 h. The mixture was poured on water (100ml) and extracted three times with ether. The water phase was furtherextracted two times with ether followed by a filtration of the waterphase. The crystals isolated by filtration of the water phase and thecrystals isolated by evaporation of the two last ether extractions weremixed giving (2) (9.2 g), m.p. 136.5°-137.5° C.

In the same way the following 1-substituted2-chloroindole-3-carbaldehydes were prepared.

1-Methyl-2-chloroindole-3-carbaldehyde (3)

Prepared from (1) (18 g), methyl iodide (17.1 g) and Nail (2.88 g)yielding (3) (18.2 g), m.p. 88°-90° C.

1-Cyclopropylmethyl-2-chloroindole-3-carbaldehyde (4)

Prepared from (1) (18 g), cyclopropylmethyl bromide (16.2 g) and NaH(2.8 g) yielding (4) (23 g), m.p. 108°-109° C.

In this reaction THF was used as solvent in stead of DMF and thereaction mixture was partly evaporated before treatment with water.

EXAMPLE 2 Methyl 8-benzylthieno[2,3-b]indole-2-carboxylate (5)

(2) (9.2 g)dissolved in methanol (100 ml) and K₂ CO₃ (10.2 g) weremixed, methyl 2-mercapto acetate (4.7 g) was added and the mixture wasstirred overnight. Water (100 ml) was added and the mixture stirred forfurther 2 h. The mixture was then filtered and the precipitate rinsedthoroughly with water and dried in vacuo at 100° C. giving (5) (10 g) asslight pink crystals, m.p. 158.3°-158.8° C.

The following thieno[2,3-b]indolecarboxylates were prepared in the sameway:

Methyl 8-methylthieno[2,3-b]indole-2-carboxylate (6)

Prepared from (3) (9.6 g), K₂ CO₃ (15 g) and methyl 2-mercaptoacetate(10 ml) yielding (6) (9.3 g), m.p. 133.5°-133.8° C.

Methyl 8-cyclopropylmethylthieno[2,3-b]indole-2-carboxylate (7)

Prepared from (4) (6.5 g), K₂ CO₃ (10 g) and methyl 2-mercaptoacetate(3.2 ml) yielding (7) (6 g), m.p. 110°-111° C.

EXAMPLE 3 8-Benzylthieno[2,3-b]indole-2-carboxylic acid (8)

KOH (3 g) was dissolved in methanol-water (1/1) (50 ml). (5) (3 g) wasadded and the mixture refluxed until the compound was in solution andsubsequently 1 h in addition. After cooling the mixture was acidifiedwith acetic acid to pH=6, and the mixture was stirred overnight. Theformed precipitate was filtered off, washed with water and dried invacuo at 50° C. The crude product (3 g) was boiled in water once more,cooled, filtered and dried again giving analytically pure (8), m.p.194-195° C.

In the same way the following thieno[2,3-b]indole-2-carboxylic acidswere prepared:

8-Methylthieno[2,3-b]indole-2-carboxylic acid (9)

Prepared from (6) (2.1 g) after reflux for 3 h yielding (9) (1.9 g)after rinse up, m.p. 179°-180° C.

EXAMPLE 4 8-Benzylthieno[2,3-b]indole-2-carbonyl chloride (10)

(8) (1 g) was dissolved in SOCl₂ (20 ml) and the mixture was stirredovernight at RT. The mixture was subsequently evaporated to dryness, theresidue treated with acetone resulting in a small amount of colourlessresidue which was filtered off. The filtrate was evaporated to drynessresulting in dark purple crystals which are used for further reactionswithout additional rinse up. Yielding (10) (0.95 g).

8-Benzylthieno[2,3-b]indole-2-carboxamide (11)

(10) 0.5 g was dissolved in acetone. An aqueous solution of NH₃ (25%, 3ml) was added and the mixture was stirred at RT for 1 h. Water was addedresulting in precipitation. After further 0.5 h stirring the precipitatewas filtered off washed with water and dried in vacuo yielding 0.47 g(11), m.p. 206.7°-207.3° C.

8-Benzylthieno[2,3-b]indole-2-(N',N'-dimethyl-3-aminopropyl)-N-(12)

(10) (0.45 g) was reacted with 3-dimethylaminopropaneamine (0.17 g) inacetone by stirring overnight at RT. By addition of water to thereaction mixture a brownish oil separated. The oil was treated withpentane resulting in brown hygroscopic crystals. Reprecipitation frommethanol/acetone/pentane gave 0.34 g crystals corresponding to thedihydrate of (12) according to the elemental analysis, m.p. 212.2-214.0°C.

8-Benzyl-2-(4-methyl-1-piperazinylcarbonyl)thieno[2,3-b]indole (13)

(10) (0.5 g) and 4-methylpiperazine (0.3 g) were stirred in acetone (50ml) overnight. Treatment with water resulted in an oil. The mixture wasextracted three times with ether, the etheral layers dried with MgSO₄filtered and evaporated to dryness. The resulting crude (13) (0.55 g)was recrystallised from acetone-pentane and subsequently precipitated asthe hydrochloride from acetone solution, m.p. 222°-224° C.

8-Benzylthieno[2,3-b]indole-2-(N-dimethylaminopropyl-N-methylcarboxamide) (14)

(10) (0.5 g) and N-methyl-3-dimethylaminopropaneamine (0.2 g) werestirred in acetone at RT for 2 days. The mixture was evaporated andsubsequently purified on a silica gel column usingdichloromethane/methanol (4/1) as eluent. After evaporation of solventand precipitation as the hydrochloride from acetone/methanol/pentane(0.4 g) (14) was isolated, m.p. 172°-174° C.

8-Benzyl-2-morpholinocarbonylthieno[2,3-b]indole (15)

(10) (1.6 g) was heated to 80° C. together with morpholine (2 ml) in drytoluene. The mixture was cooled resulting in precipitation of (15) (1.5g), m.p. 199°-201° C.

8-Benzylthieno[2,3-b]indole-2-N-ethylcarboxamide (16)

(10) (1 g) was treated with ethylamine hydrochloride (3 g) in toluene(30 ml), triethylamine (4 ml) was added and the mixture heated to 80° C.for 0.5 h. Cooling followed by filtration resulted in (16) (0.85 g),m.p. 175°-176° C.

8-Benzyl-2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)thieno[2,3-b]indole (17)

(8) (2 g) was treated with SOCl₂ (10 ml) by stirring at RT for 1 min.Excess SOCl₂ was evaporated and toluene (40 ml) followed bycyclopropylamide oxime (1.5 g) and triethylamine (2 ml) were added.Stirring at RT for 0.5 h followed by heating for 0.5 h at 80° C.resulted in a precipitate which was filtered off and treated with dryxylene (30 ml) by heating to 130° C. for 5 h. Evaporation to drynessgave an oil which after treatment with methanol gave (17) (1.5 g) as acrystalline compound, m.p. 140°-141° C.

Isopropyl 8-benzylthieno[2,3-b]indole-2-carboxylate (18)

(5) (1 g) was mixed with titanium(IV)isopropoxide ((4 ml) and IPA (50ml). Reflux for 6 h followed by evaporation of IPA and treatment withwater and subsequent filtration resulted in a crystalline mass which wasdried. Subsequent trituration with dichloromethane, isolation of organicphases, evaporation to dryness followed by trituration of the residuewith petrol ether resulted in (18) (0.9 g), m.p. 88°-89° C.

EXAMPLE 5 Methyl thieno[2,3-b]indole-2-carboxylate (19)

(5) (4.5 g) was dissolved in toluene (150 ml) and aluminium chloride(9.35 g) was added and the mixture stirred at RT overnight. Methanol (50ml) was added cautiously and after termination of the heat developmentthe reaction mixture was evaporated and extracted with water/ethylacetate twice. The organic phases dried with MgSO₄ and evaporated. Theresidue was treated with methanol filtered and the filtrate evaporated.Addition of a small amount of methanol resulted in precipitation of (19)(2.6 g), m.p. 200°-201° C.

Methyl 8-benzenesulphonylthieno[2,3-b]indole-2-carboxylate (20)

(19) (0.5 g) was added to a slurry of NaH (0.06 g)in dry THF.Benzenesulphonyl chloride (0.39 g) was added dropwise and the mixturestirred at RT overnight. Addition of water resulted in formation of aprecipitate which was filtered off and dried, resulting in (20) (0.8 g),m.p. 195.1°-197.2° C.

Methyl 8-benzoylthieno[2,3-b]indole-2-carboxylate (21)

Prepared analogously to (20) from (19) (0.5 g), 0.06 g NaH and 0.46 gbenzoyl chloride afforded (0.7 g)(21), m.p. 149.5°-151.2° C.

Methyl 8-acetylthieno[2,3-b]indole-2-carboxylate (22)

Preparation as described for (21) from (19) (0.5 g), acetyl chloride(0.17 g) and NaH (0.06 g) resulted in (22) (0.55 g), m.p. 179°-181° C.

2-Morpholinocarbonylthieno[2,3-b]indole (23)

(15) (0.5 g) was treated with AlCl₃ (1.5 g) as described for thepreparation of (19). The product arising from the ethyl acetateextraction was purified on silica gel using ethyl acetate as eluentresulting in 0.2 g of (23), m.p. 92-95° C.

EXAMPLE 6 8-Benzylthieno[2,3-b]indole-2-carbonitrile (24)

(8) (3 g) was mixed with acetonitrile (100 ml) followed by addition ofchlorosulphonyl isocyanate (1.62 g). The mixture was stirred overnightat RT whereafter triethyl amine (1.46 g) was added and the mixturestirred overnight at RT. The mixture was evaporated extracted threetimes with NaOH/ether, the combined etheral layers were evaporatedfollowed by rinse up on silica gel using pentane/triethylamine (15/1) aseluent. The residue after evaporation of the eluent was treated withether resulting in (24) (1.15 g), m.p. 130°-132° C.

8-Benzyl-2-(5-tetrazolyl)thieno[2,3-b]indole (25)

(24) (0.3 g)in chloroform (50 ml) was treated with NaN₃ (0.42 g) and NH₄CI (0.36 g) by stirring at reflux overnight. The mixture was evaporatedfollowed by addition of water and acidifying with acetic acid resultingin preparation of yellow crystals (0.32 g). The crystals were purifiedon silica gel using dichloromethane/methanol (4/1) as eluent yielding0.07 g pure (25), m.p. 277°-280° C. (decomp.).

EXAMPLE 7 8-Methylthieno[2,3-b]indole-2-carbonyl chloride (26)

Preparation as described for (10) from (9) (2.0 g) and 20 ml SOCl₂ gave2.1 g (26) which was used without further purification.

8-Methyl-2-morpholinocarbonylthieno[2,3-b]indole (27)

(26) (0.7 g) was mixed with morpholine (0.29 g)in acetone (100 ml) andstirred at RT overnight. The reaction mixture was evaporated and treatedwith NaOH whereafter it was extracted with ether and subsequentlydichloromethane. The organic phases were mixed and evaporated yieldingan oil, which was purified on silica gel using dichloromethane/ether(1/1) as eluent. After evaporation of the eluent 0.35 g of (27) wasisolated as brownish crystals, m.p. 125°-127° C.

8-Methylthieno[2,3-b]indole-2-(N-methylcarboxamide) (28)

Preparation as described for (27) from (26) (0.7 g) and methylamine(gas) which was bobbled through the acetone solution until a clearsolution was obtained. Rinse up on column with dichloromethane/methanol(9/1) as eluent. After evaporation of eluent the residue wasreprecipitated from acetone-pentane yielding (28) (0.36 g), m.p.217°-219° C.

8-Methylthieno[2,3-b]indole-2-(N,N-dimethylcarboxamide) (29)

Preparation as described for (28) from (26) (0.7 g) and dimethylamine(gas). After termination of the addition of dimethyl amine the mixturewas stirred at RT for 3 days. After rinse up on column andreprecipitation 0.44 g (29) was isolated, m.p. 151.5°-152.0° C.

8-Methylthieno[2,3-b]indole-2-(N-phenylcarboxamide) (30)

Preparation as described for (27) from (26) (0.96 g) and aniline (0.43g), stirring at RT for 14 days. Reprecipitation from acetone-pentanegave (30) (0.45 g), m.p. 199.0°-199.4° C.

8-Methyl-2-(4-methyl-1-piperazinylcarbonyl )thieno[2,3-b ]indole (31)

Preparation as for (30) from (26) (0.96 g) and N-methylpiperazine (0.46g), stirring for 14 days, rinse up on silica gel column usingdichloromethane/methanol (9/1) as eluent. Precipitation as the oxalatesalt gave (31) (0.78 g), m.p. 219.1°-219.5° C.

8-Methyl-2-morpholinomethylthieno[2,3-b]indole (32)

(27) (0.8 g) was dissolved in THF (dry, 100 ml), LiAlH₄ (0.1 g) wasadded and the mixture stirred at RT for 1 h followed by refluxovernight. The reaction mixture was rinsed up using the normal procedure(water/NaOH). After filtration the filtrate was purified on silica gelusing ethyl acetate/toluene (1/1) as eluent. 0.05 g (32) was isolatedafter precipitation and further 0.18 g by evaporation of the filtrate,m.p. 102.5°-106.0° C.

EXAMPLE 8 8-Benzyl-2-hydroxymethylthieno[2,3-b]indole (33)

(8) (0.9 g) was reduced with LiAlH₄ (1.2 g)in THF (50 ml) by stirring atRT overnight. After rinse up and filtration the filtrate was evaporatedand purified on silica gel using ether as eluent. Precipitation fromether-pentane gave (33) (0.22 g), m.p. 81°-82° C.

Methyl 8-methyl-5-methoxythieno[2,3-b]indole-2-carboxylate (34)

5-Hydroxyindolone (0.87 g) dissolved in DMF (10 ml) was added to asolution of POCl₃ (20 ml), DMF (10 ml) and dichloromethane (10 ml) keptat 0° C. The reaction mixture was stirred at 0° C. for 1 h andsubsequently at RT for 1 h. The mixture was then poured on water,neutralised with NaHCO₃ and stirred overnight, extraction withdichloromethane followed by purification on silica gel using CH₂ Cl₂ /CH₃ OH (9/1) as eluent resulted in 0.4 g crystals. These were addedslowly to a solution of NaH (0.12 g) in DMF (30 ml) followed by additionof methyl iodide (0.64 g). The mixture was stirred at RT overnight,water (100 ml) was added and the resulting mixture extracted withdichloromethane. The combined organic phases were dried with MgSO₄ andevaporated to dryness resulting in 0.27 g yellow crystals. Thesecrystals were dissolved in methanol (50 ml), K₂ CO₃ (0,35 g) and methylmercaptoacetate (0.15 g) were added and the resulting mixture stirredovernight at RT. Water (100 ml) was added and the mixture stirred for 2h followed by filtration. The resulting crystals were dried in vacuoyielding 0.2 g (34), m.p. 124°-125° C.

8-Benzylthieno[2,3-b]indole (35)

(8) (1.0 g) was heated for 2 h at 200° C. in quinoline (30 ml) with Cu(0.12 g) added. After cooling overnight the mixture was filtered,dichloromethane was added and the mixture extracted with dilute HCl andsubsequently water. The organic phase was dried (MgSO₄) and evaporatedyielding brown crystals, which were recrystallised from ethanol/water(1/1) resulting in (35) (0.3 g) as slight grey crystals, m.p.96°-98° C.

Ethyl 8-methylthieno[2,3-b]indole-2-carboxylate (36)

(6) (1 g), sodium ethoxide (0.5 g) and acetamide oxime (1 g) wererefluxed together in ethanol (100 ml) to which crushed molecular sieves(0.5 g) was added. After reflux for 2 h and subsequent stirring at RTovernight the mixture was filtered and evaporated. Extraction withwater/dichloromethane, followed by evaporation of the organic phasesresulted in a crystalline mass which was rinsed on silica gel usingdichloromethane as eluent. Yield 0.5 g of (36), m.p. 99°-100° C.

8-Methyl-2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[2,3-b]indole (37)

Repeating the procedure mentioned above for (36) using freshly preparedsodium ethoxide (from Na (0.26 g)in ethanol (50 ml)) and using refluxfor 3 days followed by the same rinse up procedure as above, resulted in(37) (0.1 g), m.p. 199.8°-200.7° C.

Thieno[2,3-b]indole (38)

(23) (0.25 g) was heated to 110° C. in morpholine (3 ml) for 20 h. Themixture was poured on water, filtered and dried followed by rinse up onsilica gel with dichloromethane as eluent, evaporation of the solventresulted in (38) (0.05 g), m.p. 210°-211° C.

EXAMPLE 9 Methyl 8-benzyl-5-bromothieno[2,3-b]indole-2-carboxylate (39)

(5) (0.5 g) was dissolved in dichloromethane (30 ml), NBS (0.7 g) wasadded and the mixture stirred at RT for 0.5 h. Addition of water,separation of the organic phase which was subsequently washed withNaHCO₃ and dried with MgSO₄ and evaporated resulted in (39) (0.5 g),m.p. 134°-135° C.

8-Benzyl-5,6-dibromothieno[2,3-b]indole-2-carboxylic acid (40)

(5) (1 g) was treated with NBS (1.4 g) by stirring overnight at RT inCH₂ Cl₂ (50 ml), filtration and evaporation resulted in 2 g of themethyl ester of (40) as yellow crystals which were washed with methanol,0.5 g of these crystals were hydrolysed with KOH as described for (8)yielding 0.4 g of (40) after drying, m.p. 269°-273° C.

Methyl 5-bromothieno[2,3-b]indole-2-carboxylate (41)

Prepared from (39) (1 g) by means of AlCl₃ (2 g) as described for (19)gave 0.15 g of (41), m.p. 216°-218° C.

Thieno[2,3-b]indole-2-(N-ethylcarboxamide) (42)

Prepared from (16) (0.5 g) and AlCl₃ (1.5 g) as described above resultedin 0.2 g of (42), m.p. 253°-254° C.

EXAMPLE 10 1-Methyl-4,6-dichloro-1,3-dihydroindol-2-one (43)

1-Methyl-4,6-dichloroisatin (4.0 g) was suspended in dry ethanol (40ml), hydrazine (9 ml) was added and the mixture was refluxed in 6 h. Themixture was then added slowly at 70° C. to a solution of sodium (1.74g)in dry ethanol (80 ml) and refluxed overnight. The reaction mixturewas cooled to room temperature, water (50 ml) was added and the volumewas reduced to about one third by evaporation. The mixture was thenpoured onto icewater (1000 ml) and acidified with 6M HCl (pH=1). Theprecipitate was filtered off washed with water and dried to afford 3.27g (87%) of (43). M.p. 144°-145° C.

In the same way 1-methyl-7-chloro-1,3-dihydroindol-2-one (44) wasprepared from 1-methyl-7-chloroisatin (10 g), hydrazine (25 ml) andsodium (5.1 g) yielding 8.1 g (88%) of (44). M.p. 111°-113° C.

EXAMPLE 11 1-Methyl-2,5-dichloroindole-3-carbaldehyde (45)

POCl₃ (6 ml) was added dropwise to a mixture of dry DMF (5.9 ml) anddichloromethane (5.9 ml) kept at 0° C.1-Methyl-5-chloro-1,3-dihydroindol-2-one (4.0 g) dissolved indichloromethane (20 ml) and pyridine (2.9 ml) was added dropwise at 0°C. over a period of 30 min. Subsequent stirring at room temperature for3h. The mixture was poured onto icewater (500 ml) neutralized withNaHCO₃ whereafter the mixture was stirred overnight. The precipitate wasfiltered off, washed with water and dried. The crude material (4.45 g)was recrystallized from ethanol yielding 1.27 g (25.4%) of (45). M.p.165°-167° C.

In the same way the following substituted 2-chloroindole-3-carbaldehydeswere prepared:

1,5-Dimethyl-2-chloroindole-3-carbaldehyde (46)

Prepared from POCl₃ (1.7 ml), DMF (1.6 ml),1,5-dimethyl-1,3-dihydroindol-2-one (1.0 g) yielding (46) 1.0 g (78%).M.p. 120°-121° C. as crude product sufficiently pure for the nextsynthesis.

1-Methyl-2,7-dichloroindole-3-carbaldehyde (47)

Prepared from POCl₃ (17 ml), DMF (17 ml), (44) (7.5 g), yielding (47)6.8 g (72%). M.p. 185°-187° C. In this reaction the reaction time was 48h instead of 3 h.

1-Methyl-2,4,6-trichloroindole-3-carbaldehyde (48)

Prepared from POCl₃ (11 ml), DMF (11 ml), (43) (8.4 g), yielding (48)6.5 g as crude product sufficiently pure for the next synthesis. ¹ H-NMR(DMSO-d₆): δ3.8 (s, 3H), 7.43 (d, 1H), 7.86 (d, 1H), 10.52 (s, 1H). Inthis reaction the reaction time was 24 h instead of 3 h.

EXAMPLE 12 Methyl 5-chloro-8-methylthieno[2,3-b]indole-2-carboxylate(49)

(45) (1.0 g) and K₂ CO₃ (1.71 g) was suspended in methanol (20 ml),methyl 2-mercaptoacetate (0.68 ml) was added and the mixture stirred 2h. Water (20 ml) was added and the mixture stirred for further 0.5 h.The precipitate was filtered off, washed with water and dried to give1.04 g (85%) of (49). M.p. 188°-190° C. (recrystallized from methanol).

In the same way the following substitutedthienol[2,3-b]indole-2carboxylates were prepared:

Methyl 7-chloro-8-methylthieno[2,3-b]indole-2-carboxylate (50)

Prepared from (47) (6.5 g), K₂ CO₃ (11.17 g) and methyl2-mercaptoacetate (4.46 ml) yielding (50) 6.62 g (83%). M.p. 166°-168°C.

Methyl 8-phenylthieno[2,3-b]indole-2-carboxylate (51)

Prepared from 1-Phenyl-2-chloroindole-3-carbaldehyde (0.90 g), K₂ CO₃(1.38 g) and methyl 2-mercaptoacetate (0.55 ml) yielding (51) 0.86 g(79.6%). M.p. 147°-149° C.

Methyl 5-methyl-8-methylthieno[2,3-b]indole-2-carboxylate (52)

Prepared from (46) (0.80 g), K₂ CO₃ (1.5 g) and methyl 2-mercaptoacetate(0.60 ml) yielding (52) 0.144 g (14.4%). M.p. 152°-155° C.

Methyl 4, 6-dichloro-8-methylthieno[2,3-b]indole-2-carboxylate (53)

Prepared from (48) (6.5 g), K₂ CO₃ (9.59 g) and methyl 2-mercaptoacetate(3.82 ml) yielding (53) 2.5 g (32.5%). M.p. 231°-232° C. The product waspurified by chromatography on silicagel using toluene as eluent. Thecompound was crystallized by trituration with methanol.

EXAMPLE 13 5-Chloro-8-methylthieno[2,3-b]indole-2-carboxylic acid (54)

KOH (0.57 g) was dissolved in methanol-water (1/1) (10 ml). (49) (0.50g) was added and the mixture refluxed for 13/4 h. After cooling themixture was acidified with 1M HCl to pH=1. The precipitate was filteredoff, washed with water and dried to give 0.44 g (93%) of (54). M.p.259°-262° C.

In the same way the following substitutedthieno[2,3-b]indole-2-carboxylic acids were prepared, with the exceptionof that the reaction mixture was acidified with acetic acid to pH=5.

5-Methyl-8-methylthieno[2,3-b]indole-2-carboxylic acid (55)

Prepared from KOH (0.40 g), (52) (0.33 g) yielding (55) 0.312 g (100%).M.p. 216°-219° C.

4,6-Dichloro-8-methylthieno[2,3-b]indole-2-carboxylic acid (56)

Prepared from KOH (2.23 g), (53) (2.20 g) after reflux for 41/3 hyielding (56) 1.67 g (79.5%). M.p. 278°-281° C.

7-Chloro-8-methylthieno[2,3-b]indole-2-carboxylic acid (57)

Prepared from KOH (4.73 g), (50) (5.9 g) after reflux overnight yielding(57) 5.54 g (99.3%). M.p. 233°-234° C.

8-Phenylthieno[2,3-b]indole-2-carboxylic acid (58)

Prepared from KOH (0.51 g), (51) (0.70 g) after reflux overnightyielding (58) 0.63 g (94%). M.p. 206°-207° C.

EXAMPLE 14 5-Chloro-8-methyl-2-morpholinocarbonylthieno[2,3-b]indole(59)

(54) (0.20 g) was dissolved in SOCl₂ (5 ml), DMF (1 μl) was added andthe mixture was stirred 2 h at room temperature and 1 h at 50° C. Themixture was subsequently evaporated to dryness, the residue strippedwith THF (10 ml) and dissolved in THF (5 ml) then morpholine (0.15 ml)was added. The mixture was stirred 21/2 h at room temperature,evaporated to dryness and extracted with dichloromethane/water. Theorganic phase was subsequently washed with 1M NaOH and 1M HCl, driedwith MgSO₄ and evaporated. The residue was treated with ethanol andfiltered to give 0.185 g (74%) of (59). M.p. 178°-182° C.

5,8-Dimethyl-2-morpholinocarbonylthieno[2,3-b]indole (60)

(55) (0.295 g) was dissolved in SOCl₂ (6 ml), DMF (1 μl) was added andthe mixture was stirred 2.5 h at room temperature and 0.5 h at 50° C.The mixture was subsequently evaporated to dryness, the residue strippedwith toluene (10 ml) and dissolved in THF (5 ml) then morpholine (0.21ml) was added. The mixture was stirred 1.5 h at room temperature,evaporated to dryness and extracted with dichloromethane/water. Theorganic phase was subsequently washed with 1M NaOH and 1M HCl, driedwith MgSO₄ and evaporated. The residue was purified by chromatography onsilical gel using toluene/ethylacetate 75/25 as eluent. The product wastreated with ethanol and filtered to give 0.225 g (65%) of (60). M.p.158°-160° C.

4, 6-Dichloro-8-methyl-2-morpholinocarbonylthieno[2,3-b]indole (61)

(56) (1.00 g) was suspended in SOCl₂ (20 ml), DMF (1 drop) was added andthe mixture was stirred 2 h at room temperature, 1 h at 50° C. andrefluxed 1 h. The mixture was evaporated to dryness and dissolved in THF(15 ml) then morpholine (0.60 ml) was added. After stirring overnightthe precipitate was filtered off, and recrystallized from aceticacid/water to afford 0.357 g (29%) of (61). M.p. 224°-226° C.

8-Phenyl-2-morpholinocarbonylthieno[2,3-b]indole (62)

(58) (0.44 g) was dissolved in SOCl₂ (3.4 ml) and stirred for 72 h. Themixture was evaporated to dryness and the residue was stripped two timeswith acetone (5 ml) and dissolved in acetone (10 ml). Morpholine (0.28ml) was added and the mixture was stirred for 72 h, evaporated todryness and extracted with dichloromethane/aqueous NaHCO₃ solution. Theorganic phase was washed with 1M NaOH and 1M HCl, evaporated to drynessand purified by chromatography on silica gel using dichloromethane/ether1/1 as eluent. The product was recrystallized from acetic acid/water togive 0.196 g (37.7%) of (62). M.p. 162°-167° C.

7-Chloro-8-methyl-2-morpholinocarbonylthieno[2,3-b]indole (63)

(57) (0.35 g) was suspended in SOCl₂ (3.0 ml) and stirred for 20 h. Themixture was evaporated to dryness and the residue was stripped withtoluene (10 ml) and dissolved in THF (8 ml). Morpholine (0.216 ml) wasadded and the mixture was stirred for 72 h, evaporated to dryness andextracted with dichloromethane/water. The organic phase was washed with1M NaOH and 1M HCl, dried with Na₂ SO₄ and evaporated to dryness. Thecrude product was recrystallized from acetic acid/water to give 0.33 g(87%) of (63). M.p. 140°-143° C.

EXAMPLE 15 Methyl 5-acetyl-8-methylthieno[2,3-b]indole-2-carboxylate(64)

To a slurry of 870 mg AlCl₃ in 50 ml dry 1,2-dichloroethane was added465 μl acetyl chloride. The mixture was stirred for 30 min. at roomtemperature. 800 mg of (6) was added, and stirring continued overnight.Another 870 mg AlCl₃ and 465 μl acetyl chloride was added, and stirringcontinued overnight. Water was added, and the organic phase dried andevaporated to dryness giving a brown powder, which was crystallized fromacetic acid and petrol ether giving (64). Yield 210 mg. M.p. 196-8° C.

EXAMPLE 16 2-Chloro-5-nitroindole-3-carbaldehyde (65)

15 g of (1) was added to a mixture of 150 ml acetic acid and 150 ml ofacetic anhydride at 0°. 3.5 ml of 100% HNO₃ was slowly added, and after1 hour another 3.5 ml of 100% HNO₃ was added. Stirring was continued for1 hour at 0° C. The mixture was then added to ice, left in the coldovernight, and filtered to give 10 g of (65), which was used withoutfurther purification.

2-Chloro-1-methyl-5-nitroindole-3-carbaldehyde (66)

To 5 g of (65) in 100 ml THF was added 550 mg NaH and 2.5 mlmethyliodide. The reaction was left with stirring overnight. Most of theTHF was evaporated off, water was added, and the water phase extractedwith EtOAc. The water phase was then acidified with acetic acid, whichprecipitated the pure product. Filtration and drying gave 770 mg of(66).

Methyl 8-methyl-5-nitrothieno[2,3-b]indole-2-carboxylate (67)

1.4 g of (66) was added to a slurry of excess K₂ CO₃ in 100 ml of MeOH.2 ml of methyl 2-mercaptoacetate was added and the mixture left withstirring overnight. Addition of water precipitated the product, whichwas washed with MeOH and water to give 640 mg of (67). M.p. 269°-71° C.

EXAMPLE 17 8-Methyl-5-nitrothieno[2,3-b]indole-2-carboxylic acid (68)

480 mg of (67) was hydrolyzed in a mixture of NaH in 25 ml of morpholineat 65° C. for 8 hours, in an attempt to directly produce themorpholino-amide. Addition of water and acidification with acetic acidprecipitated (68), yield 280 mg, which was used without furtherpurification.

8-Methyl-2-morpholinocarbonyl-5-nitrothieno[2,3-b]indole (69)

280 mg of (68) was added to 25 ml of THF, 0.5 ml of SOCl₂ was added, andthe reaction left with stirring for 1 hour. 1 ml of morpholine was addedin portions, and stirring continued. The precipitated morpholinehydrochloride was filtered off, and the solvent evaporated. The residuewas purified by column chromatography on silica gel, using MeOH in CH₂Cl₂, 1+9 as the eluent. MeOH was added to the pooled fractions toprecipitate the product, giving after filtration and drying 50 mg of(69). M.p. 250°-2° C.

EXAMPLE 18 Methyl 5-bromo-8-methylthieno[2,3]indole-2-carboxylate (70)

1.3 g N-bromosuccinimide and 1.7 g (6) was reacted in 25 ml CH₂ Cl₂ for30 min. Water was added, and the organic phase washed with saturatedNaHCO₃ solution and water. Drying and evaporation gave 1.8 g of product,which was dissolved in MeOH and precipitated by adding of water. Yield1.6 g of (70), which was used without further purification.

5-Bromo-8-methylthieno[2,3]indole-2-carboxylic acid (71)

2.5 g of (70) was hydrolyzed during 3 hours at reflux in a mixture of 25ml 4 N NaOH and 100 ml MeOH/water 1+1. After cooling to room temperatureand acidification with acetic acid the product precipitated. Filtrationand drying gave 2.4 g of (71). M.p. 229°-41° C.

5-Bromo-8-methyl-2-morpholinocarbonylthieno[2,3-b]indole (72)

To 2 g of (71) in 50 ml THF was added 5 ml of SOCl₂, and the reactionwas left with stirring overnight. Another 5 ml of SOCl₂ was added, andthe reaction left with stirring for 3 days. The solvent was evaporated,the remanence taken up in THF and 30 ml of morpholine was added. Thereaction was then left with stirring overnight. The precipitate wasfiltered off, and the filtrate evaporated to give 1.7 g of product,which was recrystallized in acetic acid-water, filtered and washed inMeOH to give 1.1 g of (72). M.p. 184° C.

EXAMPLE 19 8-Methylthieno[2,3-b]indole (73)

A slurry of 5 g of (9) and 650 ml of copper powder in 50 ml quinolinewas heated to 200° C. for 4 hours. To the cooled reaction mixture wasadded 150 ml of CH₂ Cl₂, and the mixture was washed with 1 Nhydrochloric acid (3×100 ml), water (100 ml), dried and evaporated.Recrystallization from EtOH/water gave 500 mg of a byproduct, which wasdiscarded. Addition of EtOH gave two precipitates of (73), which wascombined. Yield 1.5 g. M.p. 65.5°-66.8° C.

8-Methyl-3-trifluoroacetylthieno[2,3-b]indole (74)

A mixture of 1 g of (73) and 1.1 g of2-trifluoromethylcarbonyloxypyridine, prepared according to theliterature (Keumi, T. et. al. Chem. Lett. 5 (1990) 783-6), in 25 ml of1,2-dichloroethane, was cooled to -10° C. with stirring. 1.5 g of AlCl₃was added over 15 minutes at this temperature, the reaction mixture wasstirred at 0° C. for 4 hours, and at room temperature overnight. Waterwas added, the phases separated, and the organic phase dried andevaporated to dryness. Purification by column chromatography on silicagel in toluene gave the pure (74). Yield 590 mg. M.p. 138°-40° C.

EXAMPLE 20 3-Acetyl-2-chloroindole (75)

13.7 ml POCl₃ was slowly added to a mixture of dimethylacetamide (5.6ml) in 25 ml of chloroform, at 5° C. A solution of 6.66 g of oxindole in25 ml chloroform was slowly added, and the reaction refluxed for 7hours, and left overnight at room temperature with stirring. Thereaction mixture was added to 250 ml of ice/water, the phases separated,and the organic phase extracted with water (4×50 ml). The aqueous phaseswere pooled and neutralized with sodium acetate, and stirred for 4 hoursat room temperature. Filtration and drying gave (75). Yield 4.8 g.

3-Acetyl-2-chloro-1-methylindole (76)

To a slurry of 310 mg of NaH in 15 ml THF was added 1 g of (75), andthen 625 μl of methyl iodide. The reaction was left with stirring for 3days. Water was added, the product extracted with diethylether, and theether phase dried and evaporated to dryness to give (76). Yield 870 mg.

Methyl 3,8-dimethylthieno[2,3-b]indole-2-carboxylate (77)

450 μl of methyl 2-mercaptoacetate was added to a slurry of 870 mg of(76) and 1.2 g of K₂ CO₃ in 10 ml of MeOH. The reaction was stirredovernight. 30 ml of water was added, stirring continued for 1 hour, andthe product filtered off giving 160 mg of product. Recrystallizationfrom MeOH gave 30 mg of (77). M.p. 165.5°-166.8° C.

EXAMPLE 21 2-Chloro-1-(2-methoxyethoxymethyl)indole-3-carbaldehyde (78)

1 g of (1) was dissolved in 25 ml of THF, 268 mg of NaH was added, andthen 1.87 g of (2-methyloxyethyl)oxymethylchlorid. The reaction was leftwith stirring overnight, then added to a 2 N K₂ CO₃ solution. Themixture was extracted with toluene, the organic phase then washed withwater and brine, dried, and evaporated to give 1.5 g of oil. The oil wasthen extracted twice with boiling heptane, and the heptane solutionsleft for 2 hours to separate out a yellow oily phase. The heptane wasfinally decanted off, filtered, and evaporated giving 1.21 g of (78).M.p. 52.5-54° C.

Methyl8-((2-methyloxyethyl)-oxymethyl)-thieno[2,3-b]indole-2-carboxylate (79)

400 μl of methyl 2-mercaptoacetate was added to a slurry of 1 g of (78)and 1.1 g of K₂ CO₃ in 10 ml of MeOH. The reaction was stirredovernight, and then 20 ml of water was added. The mixture was extractedwith EtOAc, and the organic layer washed with water, dried andevaporated to give (79) as a yellow oil. Yield 880 mg. ¹ H-NMR (ppm):8.1(s, 1H); 7.8(d, 1H); 7.5(d, 1H); 7.3(m, 2H); 5.6(s, 2H); 3.9(s, 3H);3.5(m, 4H); 3.35(s, 3H).

EXAMPLE 22 3-Acetyl-2-chloro-1-(2-methoxyethoxymethyl)indole (80)

1 g of (75) was dissolved in 25 ml THF. 250 mg NaH was added, and then1.87 g of (2-methyloxyethyl)oxymethylchlorid. The reaction was left withstirring overnight, another 100 mg NaH was added, and the reactioncontinued another 4 hours. The reaction mixture was added to a 2N K₂ CO₃solution and extracted with toluene. The organic phase was washed withwater and brine, dried and evaporated. The resulting oil was extractedtwice with boiling heptane, cooled, filtered, and evaporated giving 1.23g of (80) as a yellow oil, ¹ H-NMR (ppm): 8.35(m, 1H); 7.44(m, 1H);7.27(m, 2H); 5.62(s, 2H); 3.58(m, 2H); 3.47(m, 2H); 3.32(s, 3H); 2.65(s,3H).

Methyl8-((2-methyloxyethyl)-oxymethyl)-3-methylthieno[2,3-b]indole-2carboxylate(81)

400 μl of methyl 2-mercaptoacetate was added to a slurry of 1050 mg of(80) and 1.1 g of K₂ CO₃ in 10 ml of MeOH, and left with stirring for 48hours. 20 ml of water was added, and the precipitate filtered off anddried. This material was thoroughly washed with pentane, filtered,dried, and recrystallized from EtOH giving 230 mg of (81) as a whitepowder. M.p. 85.4°-86° C.

EXAMPLE 23 1-Benzyl-2-chloro-3-acetylindole (82)

To a slurry of 400 mg of NaH in 20 ml THF was added 1 g of (75), andthen 770 μl of benzyl bromide. The reaction was left with stirring for 3days. Water was added, and the product extracted with diethylether,dried, and the solvent evaporated off to give 1.52 g of a redbrownpowder, which was used without further purification.

Methyl 8-benzyl-3-methylthieno[2,3-b]indole-2-carboxylate (83)

550 μl of methyl 2-mercaptoacetate was added to a slurry of 1.45 g of(82) and 1.6 g of K₂ CO₃ in 15 ml of MeOH, and left with stirringovernight. 30 ml of water was added, and the product isolated as asticky lump. This lump was dissolved in EtOAc, washed with water, driedand evaporated to give an oil, which slowly solidified. Crystallizationfrom MeOH gave (83). Yield 330 mg. M.p. 132°-4° C.

We claim:
 1. A compound of formula I ##STR7## wherein R¹ is H; C₁₋₆-alkyl which is optionally substituted with halogen; C₂₋₆ -alkenyl; C₂₋₆-alkynyl; C₃₋₆ -cycloalkyl; C₁₋₄ -alkyl which is substituted with C₃₋₆-cycloalkyl; carboxy; --COR⁹ ; --COOR⁹ ; C₁₋₄ -alkyl substituted withdimethylamino; --R⁹ --O--R¹⁰ ; --R⁹ --O--R¹¹ ; or a ring system, whichcomprises an aromatic group, selected from the group consisting ofphenylsulfonyl, benzoyl, benzyl and phenyl, wherein the aromatic groupof the ring system is optionally substituted with C₁₋₄ -alkyl, C₁₋₄-alkoxy, halogen, carboxy or nitro, wherein R⁹, R¹⁰ and R¹¹ areindependently C₁₋₆ -alkyl;R² is carboxy; cyano; nitro; --R⁹ --O--R¹⁰ ;--COOR⁹ ; morpholinocarbonyl; thiamorpholinocarbonyl;piperazinylcarbonyl optionally substituted with C₁₋₄ -alkyl; a ringselected from the group consisting of tetrazolyl, oxadiazolyl andthiadiazolyl wherein the ring is optionally substituted with C₁₋₄ -alkylor C₃₋₆ -cycloalkyl; methyl substituted with a morpholino group; aminounsubstituted or mono or disubstituted with a C₁₋₆ -alkyl group; methylwhich is substituted with an hydroxy or an amino group wherein the aminogroup is unsubstituted or N-mono or disubstituted with a C₁₋₆ -alkylgroup; or sulfamoyl unsubstituted or mono or disubstituted with a C₁₋₆-alkyl group; wherein the C₁₋₆ -alkyl groups are independentlyoptionally substituted with halogen, phenyl, benzyl, or methyl which issubstituted with amino which is substituted with two methyl groups; R³is H; C₁₋₆ -alkyl; trifluoromethyl; trifluoroacetyl; C₁₋₆ -alkoxy;halogen; nitro; cyano; --COOR⁹ ; or amino which is unsubstituted or monoor disubstituted with C₁₋₆ -alkyl; and R⁴, R⁵, R⁶ and R⁷ independentlyare H; nitro; amino; halogen; tritium; trifluoromethyl; trifluoroacetyl;sulfo; carboxy; carbamoyl; sulfamoyl; --COR⁹ ; --COOR⁹ ; C₁₋₆ -alkoxy;or C₁₋₆ -alkyl optionally substituted with halogen; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, wherein R¹ is C₁₋₆ -alkyl optionally substituted with halogen;C₁₋₄ -alkyl which is substituted with C₃₋₆ -cycloalkyl; or a ringsystem, which comprises an aromatic group, selected from the groupconsisting of benzoyl, benzyl and phenyl, wherein the aromatic group isoptionally substituted with C₁₋₄ -alkyl, C₁₋₄ -alkoxy, halogen, carboxyor nitro.
 3. A compound according to claim 1, wherein R² is carboxy;cyano; morpholinocarbonyl; piperazinylcarbonyl optionally substitutedwith C₁₋₄ -alkyl; a ring selected from the group consisting oftetrazolyl, oxadiazolyl and thiadiazolyl wherein the ring is optionallysubstituted with C₁₋₄ -alkyl or C₃₋₆ -cycloalkyl; methyl which issubstituted with a morpholino group; amino unsubstituted or mono ordisubstituted with a C₁₋₆ -alkyl group; or methyl substituted with aminowhich is unsubstituted or N-mono or disubstituted with a C₁₋₆ -alkylgroup.
 4. A compound according to claim 3, wherein R² is carboxy; cyano;a ring selected from the group consisting of tetrazolyl, oxadiazolyl andthiadiazolyl wherein the ring is optionally substituted with C₁₋₄ -alkylor C₃₋₆ -cycloalkyl; methyl which is substituted with a morpholinogroup; amino unsubstituted or mono or disubstituted with a C₁₋₆ -alkylgroup; or methyl substituted with amino which is unsubstituted or N-monoor disubstituted with a C₁₋₆ -alkyl group.
 5. A compound according toclaim 1, wherein R³ is H; C₁₋₆ -alkyl; trifluoromethyl; C₁₋₆ -alkoxy; oramino which is unsubstituted or mono or disubstituted with C₁₋₆ -alkyl.6. The compound according to claim 1 selected from the following:Methyl8-benzylthieno[2,3-b]indole-2-carboxylate; Methyl8-methylthieno[2,3-b]indole-2-carboxylate; Methyl8-cyclopropylmethylthieno[2,3-b]indole-2-carboxylate; Isopropyl8-benzylthieno[2,3-b]indole-2-carboxylate; Methylthieno[2,3-b]indole-2-carboxylate; Methyl8-benzenesulphonylthieno[2,3-b]indole-2-carboxylate; Methyl8-benzoylthieno[2,3-b]indole-2-carboxylate; Methyl8-acetylthieno[2,3-b]indole-2-carboxylate; Methyl8-methyl-5-methoxythieno[2,3-b]indole-2-carboxylate; Ethyl8-methylthieno[2,3-b]indole-2-carboxylate;8-Methyl-2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[2,3-b]indole; Methyl8-benzyl-5-bromothieno[2,3-b]indole-2-carboxylate; Methyl5-bromothieno[2,3-b]indole-2-carboxylate; Methyl5-chloro-8-methylthieno[2,3-b]indole-2-carboxylate; Methyl7-chloro-8-methylthieno[2,3-b]indole-2-carboxylate; Methyl8-phenylthieno[2,3-b]indole-2-carboxylate; Methyl5-methyl-8-methylthieno[2,3-b]indole-2-carboxylate; Methyl4,6-dichloro-8-methylthieno[2,3-b]indole-2-carboxylate; Methyl5-acetyl-8-methylthieno[2,3-b]indole-2-carboxylate; Methyl8-methyl-5-nitrothieno[2,3-b]indole-2-carboxylate; Methyl5-bromo-8-methylthieno[2,3]indole-2-carboxylate; Methyl3,8-dimethylthieno[2,3-b]indole-2-carboxylate; Methyl8-((2-methyloxyethyl)-oxymethyl)-thieno[2,3-b]indole-2-carboxylate;Methyl 8-((2-methyloxyethyl)-oxymethyl )-3-meth ylthieno[2,3-b]indole-2carboxylate; or Methyl8-benzyl-3-methylthieno[2,3-b]indole-2-carboxylate; ora pharmaceuticallyacceptable salt thereof.
 7. The compound according to claim 1, selectedfrom the following:8-Benzylthieno[2,3-b]indole-2-carboxylic acid;8-Methylthieno[2,3-b]indole-2-carboxylic acid;8-Benzyl-2-(5-tetrazolyl)thieno[2,3-b]indole;8-Benzyl-5,6-dibromothieno[2,3-b]indole-2-carboxylic acid;5-Chloro-8-methylthieno[2,3-b]indole-2-carboxylic acid;5-Methyl-8-methylthieno[2,3-b]indole-2-carboxylic acid;4,6-Dichloro-8-methylthieno[2,3-b]indole-2-carboxylic acid;7-Chloro-8-methylthieno[2,3-b]indole-2-carboxylic acid;8-Phenylthieno[2,3-b]indole-2-carboxylic acid;8-Methyl-5-nitrothieno[2,3-b]indole-2-carboxylic acid; or5-Bromo-8-methylthieno[2,3]indole-2-carboxylic acid; orapharmaceutically acceptable salt thereof.
 8. The compound according toclaim 1 selected from thefollowing:8-Benzyl-2-(4-methyl-1-piperazinylcarbonyl)thieno[2,3-b]indole;8-Benzyl-2-morpholinocarbonylthieno[2,3-b]indole;-2-Morpholinocarbonylthieno[2,3-b]indole;8-Methyl-2-morpholinocarbonylthieno[2,3-b]indole;8-Methyl-2-(4-methyl-1-piperazinylcarbonyl)thieno[2,3-b]indole;8-Methyl-2-morpholinomethylthieno[2,3-b]indole;5-Chloro-8-methyl-2-morpholinocarbonylthieno[2,3-b]indole;5,8-Dimethyl-2-morpholinocarbonylthieno[2,3-b]indole;4,6-Dichloro-8-methyl-2-morpholinocarbonylthieno[2,3-b]indole;8-Phenyl-2-morpholinocarbonylthieno[2,3-b]indole;7-Chloro-8-methyl-2-morpholinocarbonylthieno[2,3-b]indole;8-methyl-2-morpholinocarbonyl-5-nitrothieno[2,3-b]indole; or5-Bromo-8-methyl-2-morpholinocarbonylthieno[2,3-b]indole; orapharmaceutically acceptable salt thereof.
 9. The compound according toclaim 1 selected from thefollowing:8-Benzyl-2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)thieno[2,3-b]indole;8-Benzylthieno[2,3-b]indole-2-carbonitrile; or8-Benzyl-2-hydroxymethylthieno[2,3-b]indole; ora pharmaceuticallyacceptable salt thereof.
 10. A compound of formula I ##STR8## wherein R¹is C₂₋₆ -alkenyl; C₂₋₆ -alkynyl; C₃₋₆ -cycloalkyl; C₁₋₄ -alkylsubstituted with C₃₋₆ -cycloalkyl; carboxy; --COR⁹ ; --COOR⁹ ; C₁₋₄-alkyl substituted with dimethylamino; --R⁹ --O--R¹⁰ ; --R⁹ --O--R¹⁰--O--R¹¹ or a ring system, which comprises an aromatic group, selectedfrom the group consisting of phenylsulfonyl, benzoyl, benzyl and phenyl,wherein the aromatic group is optionally substituted with C₁₋₄ -alkyl,C₁₋₄ -alkoxy, halogen, carboxy or nitro, wherein R⁹, R¹⁰ and R¹¹ areindependently C₁₋₆ -alkyl;R² is carbamoyl unsubstituted or mono ordisubstituted with a C₁₋₆ -alkyl group wherein the C₁₋₆ -alkyl group isindependently optionally substituted with halogen, phenyl, benzyl ormethyl which is substituted with amino which is substituted with twomethyl groups; R³ is H; C₁₋₆ -alkyl; trifluoromethyl; trifluoroacetyl;C₁₋₆ -alkoxy; halogen; nitro; cyano; --COOR⁹ ; or amino unsubstituted ormono or disubstituted with C₁₋₆ -alkyl; and R⁴, R⁵, R⁶ and R⁷independently are H; nitro; amino; halogen; tritium; trifluoromethyl;trifluoroacetyl; sulfo; carboxy; carbamoyl; sulfamoyl; --COR⁹ ; --COOR⁹; C₁₋₆ -alkoxy; or C₁₋₆ -alkyl optionally substituted with halogen; or apharmaceutically acceptable salt thereof.
 11. A compound according toclaim 10, wherein R¹ is C₁₋₄ -alkyl substituted with C₃₋₆ -cycloalkyl;or a ring system, which comprises an aromatic group, selected from thegroup consisting of benzoyl, benzyl and phenyl, wherein the aromaticgroup is optionally substituted with C₁₋₄ -alkyl, C₁₋₄ -alkoxy, halogen,carboxy or nitro.
 12. A compound according to claim 10, wherein R¹ is--COR⁹ ; --COOR⁹ ; or a ring system, which comprises an aromatic group,selected from the group consisting of benzoyl, benzyl and phenyl,wherein the aromatic group is optionally substituted with C₁₋₄ -alkyl,C₁₋₄ -alkoxy, halogen, carboxy or nitro, wherein R⁹, R¹⁰ and R¹¹ areindependently C₁₋₆ -alkyl; and R² is unsubstituted carbamoyl.
 13. Acompound according to claim 10, wherein R² is carbamoyl mono ordisubstituted with a C₁₋₆ -alkyl group wherein the C₁₋₆ -alkyl group isindependently optionally substituted with halogen, phenyl, benzyl ormethyl which is substituted with amino which is substituted with twomethyl groups.
 14. A compound according to claim 10, wherein R³ is H;C₁₋₆ -alkyl; trifluoromethyl; C₁₋₆ -alkoxy; or amino which isunsubstituted or mono or disubstituted with C₁₋₆ -alkyl.
 15. Thecompound according to claim 10 selected from thefollowing:8-Benzylthieno[2,3-b]indole-2-carboxamide;8-Benzylthieno[2,3-b]indole-2-(N-(N',N'-dimethyl)-3-aminopropyl)carboxamide8-Benzylthieno[2,3-b]indole-2-(N-(N',N'-dimethyl)-3-aminopropyl-N-methylcarboxamide);or 8-Benzylthieno[2,3-b]indole-2-N-ethylcarboxamide; orapharmaceutically acceptable salt thereof.
 16. A compound of formula I##STR9## wherein R¹ is C₁₋₆ -alkyl optionally substituted withhalogen;R² is carbamoyl mono or disubstituted with a C₁₋₆ -alkyl groupwherein the C₁₋₆ -alkyl group is independently optionally substitutedwith halogen, phenyl, benzyl or methyl which is substituted with aminowhich is substituted with two methyl groups; R³ is H; C₁₋₆ -alkyl;trifluoromethyl; trifluoroacetyl; C₁₋₆ -alkoxy; halogen; nitro; cyano;--COOR⁹ ; or amino unsubstituted or mono or disubstituted with C₁₋₆-alkyl; and R⁴, R⁵, R⁶ and R⁷ independently are H; nitro; amino;halogen; tritium; trifluoromethyl; trifluoroacetyl; sulfo; carboxy;carbamoyl; sulfamoyl; --COR⁹ ; --COOR⁹ ; C₁₋₆ -alkoxy; or C₁₋₆ -alkyloptionally substituted with halogen; or a pharmaceutically acceptablesalt thereof.
 17. The compound according to claim 16 selected from thefollowing:8-Methylthieno[2,3-b]indole-2-(N-methylcarboxamide);8-Methylthieno[2,3-b]indole-2-(N,N-dimethylcarboxamide); or8-Methylthieno[2,3-b]indole-2-(N-phenylcarboxamide); orpharmaceuticallyacceptable salt thereof.
 18. A pharmaceutical composition comprising apharmaceutically acceptable carrier or diluent and a compound of formulaI ##STR10## wherein R¹ is H; C₁₋₆ -alkyl optionally substituted withhalogen; C₂₋₆ -alkenyl; C₂₋₆ -alkynyl; C₃₋₆ -cycloalkyl; C₁₋₄ -alkylsubstituted with C₃₋₆ -cycloalkyl; carboxy; --COR⁹ ; --COOR⁹ ; C₁₋₄-alkyl substituted with dimethylamino; --R⁹ --O--R¹⁰ ; --R⁹ --O--R¹⁰--O--R¹¹ ; or a ring system, which comprises an aromatic group, selectedfrom the group consisting of phenylsulfonyl, benzoyl, benzyl and phenyl,wherein the aromatic group is optionally substituted with C₁₋₄ -alkyl,C₁₋₄ -alkoxy, halogen, carboxy or nitro, wherein R⁹, R¹⁰ and R¹¹ areindependently C₁₋₆ -alkyl;R² is carboxy; cyano; nitro; --R⁹ --O--R¹⁰ ;--COOR⁹ ; morpholinocarbonyl; thiamorpholinocarbonyl;piperazinylcarbonyl optionally substituted with C₁₋₄ -alkyl; a ringselected from the group consisting of tetrazolyl, oxadiazolyl andthiadiazolyl wherein the ring is optionally substituted with C₁₋₄ -alkylor C₃₋₆ -cycloalkyl; morpholinomethyl; amino unsubstituted or mono ordisubstituted with a C₁₋₆ -alkyl group; methyl substituted with aminowhich is unsubstituted or N-mono or disubstituted with a C₁₋₆ -alkylgroup; sulfamoyl unsubstituted or mono or disubstituted with a C₁₋₆-alkyl group; or carbamoyl unsubstituted or mono or disubstituted with aC₁₋₆ -alkyl group; wherein the C₁₋₆ -alkyl group(s) is/are independentlyoptionally substituted with halogen, phenyl, benzyl or methyl which issubstituted with amino which is substituted with two methyl groups; R³is H; C₁₋₆ -alkyl; trifluoromethyl; trifluoroacetyl; C₁₋₆ -alkoxy;halogen; nitro; cyano; --COOR⁹ ; or amino unsubstituted or mono ordisubstituted with C₁₋₆ -alkyl; and R⁴, R⁵, R⁶ and R⁷ independently areH; nitro; amino; halogen; tritium; trifluoromethyl; trifluoroacetyl;sulfo; carboxy; carbamoyl; sulfamoyl; --COR⁹ ; --COOR⁹ ; C₁₋₆ -alkoxy;or C₁₋₆ -alkyl optionally substituted with halogen; or apharmaceutically acceptable salt thereof.
 19. A pharmaceuticalcomposition according to claim 18 in the form of an oral dosage unit orparenteral dosage unit.
 20. A pharmaceutical composition according toclaim 19, wherein said dosage unit comprises from about 1 to about 100mg of the compound.
 21. A pharmaceutical composition according to claim18, wherein R² is carbamoyl unsubstituted or mono or disubstituted witha C₁₋₆ -alkyl group wherein the C₁₋₆ -alkyl group is independentlyoptionally substituted with halogen, phenyl, benzyl or methyl which issubstituted with amino which is substituted with two methyl groups. 22.A method of treating a disease in the central nervous system related tothe metabotropic glutamate receptor system comprising administering to asubject in need thereof an effective amount of a compound of formula I##STR11## wherein R¹ is H; C₁₋₆ -alkyl optionally substituted withhalogen; C₂₋₆ -alkenyl; C₂₋₆ -alkynyl; C₃₋₆ -cycloalkyl; C₁₋₄ -alkylsubstituted with C₃₋₆ -cycloalkyl; carboxy; --COR⁹ ; --COOR⁹ ; C₁₋₄-alkyl substituted with dimethylamino; --R⁹ --O--R¹⁰ ; --R⁹ --O--R¹⁰--O--R¹¹ ; or a ring system, which comprises an aromatic group, selectedfrom the group consisting of phenylsulfonyl, benzoyl, benzyl and phenyl,wherein the aromatic group is optionally substituted with C₁₋₄ -alkyl,C₁₋₄ -alkoxy, halogen, carboxy or nitro, wherein R⁹, R¹⁰ and R¹¹ areindependently C₁₋₆ -alkyl;R² is H; carboxy; cyano; nitro; C₁₋₆ -alkyloptionally substituted with hydroxy; --R⁹ --O--R¹⁰ ; --COOR⁹ ;morpholinocarbonyl; thiamorpholinocarbonyl; piperazinylcarbonyloptionally substituted with C₁₋₄ -alkyl; a ring selected from the groupconsisting of tetrazolyl, oxadiazolyl and thiadiazolyl wherein the ringis optionally substituted with C₁₋₄ -alkyl or C₃₋₆ -cycloalkyl;morpholinomethyl; amino unsubstituted or mono or disubstituted with aC₁₋₆ -alkyl group; methyl substituted with amino which is unsubstitutedor N-mono or disubstituted with a C₁₋₆ -alkyl group; sulfamoylunsubstituted or mono or disubstituted with a C₁₋₆ -alkyl group; orcarbamoyl unsubstituted or mono or disubstituted with a C₁₋₆ -alkylgroup; wherein the C₁₋₆ -alkyl group(s) is/are independently optionallysubstituted with halogen, phenyl, benzyl, or methyl which is substitutedwith amino which is substituted with two methyl groups; R³ is H; C₁₋₆-alkyl; trifluoromethyl; trifluoroacetyl; C₁₋₆ -alkoxy; halogen; nitro;cyano; --COOR⁹ ; or amino unsubstituted or mono or disubstituted withC₁₋₆ -alkyl; and R⁴, R⁵, R⁶ and R⁷ independently are H; nitro; amino;halogen; tritium; trifluoromethyl; trifluoroacetyl; sulfo; carboxy;carbamoyl; sulfamoyl; --COR⁹ ; --COOR⁹ ; C₁₋₆ -alkoxy; or C₁₋₆ -alkyloptionally substituted with halogen; or a pharmaceutically acceptablesalt thereof.
 23. The method according to claim 22, wherein the diseaseis epilepsy, senile dementia, Parkinson's disease, Huntington's Chorea,pain, and cerebral ischemia.